All Juiced Up

^While performance enhancing drugs made national news through Lance Armstrong’s very public doping scandel, they are also common among amateur atheletes and can easily land a patient in your ED.

Performance enhancing drugs aren’t merely the domain of home run heroes and famous cyclists anymore. Emergency toxicology experts Michael Nelson, MD, MS & Timothy Erickson, MD give a run-down of the steroids, stimulants and hormones that are likely to land an athlete in your emergency department.

A 48-year-old male presents to the emergency department complaining of bilateral hand numbness and tingling over the past few months. The patient has also noticed a mild swelling of bilateral lower extremities, worse at the end of the day and improved with leg elevation. He has no significant past medical history and takes no medications. He denies any dyspnea on exertion, orthopnea, neck pain, headaches, or chest pain. Examination reveals a well-nourished muscular man with trace bilateral lower extremity swelling and positive Tinel’s and Phalen’s sign with reproduction of numbness and tingling in his hands. Laboratory tests are within normal limits, including renal and hepatic function tests, cardiac markers, and brain natriuretic peptide, except for a blood glucose of 162 mg/dL. Chest x-ray is without acute cardiopulmonary disease. Just prior to discharge, the emergency physician casually asks the patient what he does for a living. The patient owns his own gym and was once a professional body builder. The physician then begins to question about use of supplements, hormones and steroid use. The patient admits to prior use of anabolic steroids but denies use since quitting his weight lifting career. He does use growth hormone regularly to help with reported “anti-aging” effects so he can “keep up with some of the young guys” at his gym.

Background

Over the past decade, performance-enhancing drugs (PEDs) have received a large amount of attention in the professional sports world. Multiple examples have made national headlines recently including (now vacated) Tour de France champion Lance Armstrong’s admission, Major League Baseball implementing growth hormone testing in season, and the report of the Miami New Times that Biogenesis of America, LLC provided PEDs to multiple professional athletes. The use of performance enhancers in athletic competition is not a new phenomenon. During the Ancient Olympic Games, it is reported that contestants would try herbal preparations, gorge themselves on meat (which was an uncommon practice at the time), use hallucinogens, and eat animal testicles to gain an advantage. Roman gladiators used stimulants like strychnine to fight fatigue in the arena. In 1904, marathon runner Thomas Hicks used a mixture of brandy and strychnine to win the Olympic gold medal. In 1954, reportedly the Soviet Union coach informed Dr. John Ziegler that the Soviet team was using testosterone at the World Weightlifting Championships in Vienna, Austria. Afterword, Dr. Ziegler started the United States team on testosterone and later developed Dianabol in 1958. Also in the 1950s, amphetamines, which were used by soldiers in World War II, became common to minimize the sensation of fatigue. In 1967, Tom Simpson died during the Tour de France allegedly due to amphetamine use. Subsequently, the International Olympic Committee (IOC) developed a medical commission to combat doping in sports and the first drug testing began at the 1968 Olympic games. That year, pentathlete Hans-Gunner Liljenwall became the first person disqualified (and lost his bronze medal) from the Olympic games for testing positive for alcohol, which he used to calm his nerves prior to the pistol-shooting event.

In 1975, the IOC banned anabolic steroids, and testing began in the 1976 Olympic Games in Montreal, Canada in which 11 athletes tested positive for banned substances. In 1988, sprinter Ben Johnson was stripped of his gold medal for using stanozolol. That same year, US Congress passed the Anabolic Steroids Control Act making anabolic steroids a Schedule III medication. The 1990s and 2000s are littered with a multitude of historical events in drug testing and sports, including multiple players that are suspected or confirmed of PED use. In 1999, the World Anti-Doping Agency (WADA) was formed and is responsible for maintaining and promoting the fight against doping in sports. In 2003, BALCO (Bay-area Laboratory Co-Operative) was raided which implicated multiple MLB players in PED use. President George W. Bush passes the Anabolic Steroids Control Act of 2004, which made steroid precursors and many additional steroid based drugs Schedule III medications. The 2007 Mitchell Report in Major League Baseball changed policy in baseball and public perception of many players. It even drew government involvement with individuals testifying before a House Oversight and Government Reform Committee.

Despite all the extensive media coverage for professional athletes, the more shocking statistics occur in the general population. A 2012 article in Pediatrics by Eisenberg et al. found that 34.7% of adolescents used protein powders and 5.9% used steroids. The study also concluded that in addition to a “thin ideal” with a focus on leanness, muscularity is important for body satisfaction for both adolescent boys and girls. Monitoring the Future data trends place steroid use for adolescent males between 0.6 – 2.8% over the past 20 years. Other studies cite prevalence rates as high as 4 – 11% in male and 2.5% in female adolescents. The use of PEDs doesn’t fall solely on the young. TV and media ads focus on an aging population to check for “low T” and show middle-aged men enjoying various activities after getting hormone replacement. A recent CNN video article depicts a 74 year-old physician who is using anabolic steroids and growth hormone for their anti-aging effects and is the “face” for a company Cenegenics® that made a $100 million in revenue last year.

The list of PEDs is large and includes anabolic androgenic steroids, growth hormone, stimulants, and blood doping. For a complete list, please refer to the WADA Prohibited List, which is the IOC and international standard for restricted substances in competition. Testing for these substances is also a large topic and will not be covered in this correspondence.

Various PEDs and Clinical Effects
Androgenic anabolic steroids (AAS) are commonly thought of as the protypical PED abused by athletes and are synthetic derivatives of testosterone. Many various AAS exist and come in oral and injectable formulations including Dianabol (methandrostenolone), Anadrol (oxymethalone), Oxandrin (oxandrolone), Winstrol (stanozolol), and Durabolin (nandralone). Their anabolic effects are proven and they do build muscle, increase lean body mass, induce lipolysis (but does not appear to alter fat mass), decrease fatigue, and increase erythropoiesis. Studies however do not show an increase in endurance performance with AAS. The androgenic effects, however, are also well documented and include increase in acne and body hair, deepening of the voice, male pattern baldness, hypogonadism, decreased semen production, prostate enlargement, loss of female body contour, and altered menstrual cycles. Additional adverse effects include water retention, difficulty sleeping, irritability, gynecomastia, and alteration of libido. A review by Hartgens and Kuipers in 2004 noted that at least 40% of male subjects self-reported many of these effects. Many cardiovascular effects can be seen with AAS abuse. Elevated blood pressure, cardiomyopathies, atrial fibrillation, prolongation of the QTc interval, cerebrovascular accidents, vascular thrombosis, acute heart failure, sudden cardiac death, and myocardial infarctions have all been reported. AAS can cause hepatic damage seen as cholestasis, peliosis hepatitis, hepatocellular hyperplasia, and cancer. Psychological effects are prominent with aggression, hostility, mood alterations (depression, paranoia, psychosis) and body dysmorphia. AAS users can develop addictive behaviors, dependence, and withdrawal symptoms (i.e., craving, fatigue, restlessness, headache, anorexia). Even with all of these complications, AAS use is a common practice to achieve the “ideal” muscular body and gain an edge in athletic competition.

Human growth hormone (hGH) is an endogenous hormone release in pulsatile fashion from the anterior pituitary. It produces downstream release of muscle and liver insulin growth factor-1 (IGF-1), which stimulates muscles hypertrophy via intracellular cascades that balance protein degradation and synthesis with DNA transcription. A recombinant form of hGH (rhGH, will simply refer to as GH) was developed that has the same polypeptide structure of endogenous GH. Due to the downstream effect of GH, some people will use IGF-1 directly for performance enhancement. GH release does have a positive and direct correlation with exercise and increases linearly with intensity. Age and adiposity will blunt GH response and GH release decreases by 50% roughly every 7 years after the age 25. Some of its major effects include development of linear bone growth in children, increase lipolysis and net muscle protein synthesis, divert nutrients from adipose tissue, stimulate collagen synthesis, and result in net elevation of glucose. These effects have given GH the reputation of burning fat, building muscle, increasing lean body mass, shortening recovery time, healing tissue, and having anti-aging effects. Clinical studies however have failed to show benefit in ergogenicity in non-GH deficient individuals, and even in GH deficient individuals, studies are mixed on muscle strength and exercise performance. A systematic review of 27 randomized controlled trials by Lui, et al, in 2008 found no differences in strength or exercise capacity and improvement in lean body mass was seen but likely due to water retention. Side effects however were observed in 15 – 44% of patients including soft tissue swelling, paresthesias, carpal tunnel syndrome, hypertension, joint stiffness, myalgias, insulin resistance, gynecomastia, and acromegalic changes. In trained athletes, few studies exist, and even the Mitchell Report related athletes’ impression that GH did not improve performance. Only one study by Meinhardt, et al, in 2010 demonstrated an improvement in sprint capacity in men (measured via sprint cycle ergometry/Wingate test and of unclear clinical significance in competition) but show no effect on muscle strength, power, and endurance. Despite the evidence to the contrary, athletes still believe it improves performance and continue to abuse GH. Additionally, a recent study by Brennan, et al, in 2011 found that 12% of experienced (attended a commercial gym ≥ 3 times per week) male weightlifters abused GH. Furthermore, 81% of these individuals abused AAS and 56% abused other substances such as opioids, cocaine, or 3,4-methylenedioxy-N-methylamphetamine (MDMA).

Stimulants encompass a wide variety of substances that include xanthines (caffeine), nicotine, sympathomimetics (cocaine, amphetamines, reuptake inhibitors of dopamine, norepinephrine, epinephrine, serotonin), beta-agonists (albuterol, clenbuterol), and strychnine to name a few. Most are abused to help decrease fatigue associated with vigorous work out regimens. In general stimulants can result in tachycardia, hyperthermia, hypertension, tremors, agitation, seizures, and, in severe cases, fatal dysrhythmias. Additionally a lactic acidosis and rhabdomyolysis may occur. Cocaine can block sodium channels leading to widening of the QRS complex on the electrocardiogram (ECG), which can lead to dysrhythmias. Many of the reuptake inhibitors can lead to seizures or will prolong the QTc interval precipitating Torsade de Pointes. In the case of beta-agonists and xanthines, hypokalemia may be found on laboratory examination. Strychnine causes trismus, risus sardonicus, “awake” convulsions, opisthotonus, and death typically will occur from asphyxiation. Long-term use of stimulants can lead to psychological addiction and societal decline. Additionally, cardiovascular complications may occur.

Blood doping is the practice of increasing red blood cells (RBCs) to provide higher oxygen delivery to tissues and improve aerobic capacity and endurance. This practice is done naturally via high altitude training, perhaps one of the reasons why one of the U.S. Olympic training facilities is located in Colorado. It can also be achieved via less scrupulous methods via blood transfusion or hormonal stimulation in the form of erythropoietin (EPO). Blood transfusions may be homologous or autologous and the athlete generally receives the transfusion just prior to a major sporting event. With homologous transfusions, the possibility of transfusion reactions is much higher if antibody matching is not done correctly. Additional risks include communicable diseases (hepatitis, human immunodeficiency virus) and infection if improperly stored. Autologous transfusions involve the athlete harvesting his own RBCs prior to competition. EPO will stimulate production of hemoglobin on the order of weeks to months. With elevating hematocrit concentrations, the blood becomes more viscous and can lead to cardiovascular complications (stroke, heart attack) similar to polycythemia patients.

Many other substances have been used for performance enhancement. These include alcohol, heroin, marijuana, insulin, diuretics, chorionic gonadotropin, hormone antagonists (aromatase inhibitors, selective estrogen receptor modulators), beta-blockers, and gene doping (Peroxisome Proliferator Activated Receptor beta agonists). Other over the counter supplements are used commonly by the general population and include creatine monohydrate powder, whey protein, branched chain amino acids, vitamins, minerals and herbal products. Some of these products are marketed as anabolic in nature and printed directly on the bottle. Unfortunately, nutritional supplements are not regulated by the Food and Drug Administration (FDA), and a study by Buame, et al, in 2006 showed that some of these supplements are tainted with stimulants and anabolic steroids (and would create positive antidoping tests). Even electrolyte replacement solutions (e.g., Gatorade) may be thought of as performance enhancers (and are even marketed as such), however the potential for deleterious outcomes with many of these products is much less than restricted products.

Clinical Recommendations
The mainstay of treatment for a patient presenting to the emergency department with symptoms of PED toxicity is symptom based goal directed supportive care. Benzodiazepines should be utilized for aggressiveness and agitation. Administer intravenous fluids as needed for dehydration or tachycardia. Actively cool hyperthermic patients quickly as this is associated with high morbidity and mortality. Question about co-ingestion of other substances. Check hemoglobin and electrolytes and correct metabolic derangements as indicated. In cases of xanthine or beta agonist toxicity, beta-blockers may be considered for tachycardia and hypotension.

Once PED abuse is confirmed, the physician should educate the patient about the potential dangers and long term consequences of abuse. Appropriate counseling or therapy can subsequently be established on a case-by-case basis.

Summary
Performance enhancing drugs are commonly thought of as restricted to professional competitive athletes. Their use, however, is present in the general public and shockingly enough in young adolescents and the aging population. Additionally, PEDs are not just anabolic steroids or growth hormone and can be any substance that a person ingests to gain an advantage, athletically or physically. The emergency physician should have a high degree of suspicion and question his patients about non-prescription use of supplements or PEDs. Although toxicity from these substances may present rarely to the ED, the potential for a meaningful long-term impact exists if the provider recognizes and educates about the dangers of PED abuse.